beta-haloethylamines



Patented Oct. 2, 1951 2.569.814 fi-HALOETHYLANIINES James F. Kerwin andGlenn E. Ullyot, Philadelphia, Pa., assignors to Smith, Kline & FrenchLaboratories, Philadelphia, Pa, a'corporation of Pennsylvania NoDrawing. Application December 15, 1948, Serial No. 65,508

6 Claims. 1

This invention relates to new compositions of matter having desirablephysiological properties, more particularly adrenolytic or sympatholyticproperties.

The new compounds according to this invention are p-haloethylamines withthe nitrogen linked to the 7-position of the acenaphthene ring systemand have the general formula:

general formula above such as will be readily formed with, for example,organic and inorganic acids such, as hydrochloric. sulfuric, sultamic,tartaric, hydrobromic, glycolic, phosphoric, succinic, maleic, acetic,and the like.

More specifically within the general formula above, this inventioncontemplates compounds having the following more specific formula:

in which Z is a member or the group consisting of 1. Alkyl groups havingnot in excess of 8 carbon atoms, i. e., iijethyl, ethyl, propyl, butyl,amyl, hexyl, heptyl a d octyl groups.

2. Alkenyl groups ving not in excess of 8 carbon atoms, i. e., pr penyl,butenyl, pentenyl, hexenyl, heptenyl and nyl groups.

3. Aralkyl groups the alkyl' portion of which comprises methylene,ethylene, propylene and butylene radicals, i. er the alkyl portion doesnot exceed 4 carbon atoms.

4. Substituted aralkyl grou s the alkyl portion of which comprisesmethylene, ethylene,

propylene and butylene radicals, i. e... the alkyl portion does notexceed 4 carbon atoms, and the substitution is of a member of the groupconsisting of:

(b) Ethyl, methyl, propyl and butyl.

(c) Alkoxy groups, the alkyl portion of which comprises ethyl, methyl,propyl and butyl, i. e., does not exceed 4 carbon atoms. I

(d) Fluorine.

(e) Bromine.

(f) Chlorine.

(g) Amino groups.

(h) Acylamino groups, the acyl group of which comprises formyl, acetyl,propionyl. butyryl, valeryl, caproyl, heptoyl and caprylyl, i. e., doesnot exceed 8 carbon atoms.

(1') Alkylamino groups, the alkyl portion of which comprises ethyl,methyl, propyl and butyl, i. e., does not exceed 4 carbon atoms.

5. Alkoxyethyl groups, the alkoxy portion of which comprises methoxy,ethoxy, propoxy, butoxy, amyloxy, hexyloxy, heptyloxy, and octyloxygroups; i. e., does not exceed 8 carbon atoms.

6. Aryloxyalkyl groups, the alkyl portion of which comprises ethylene,propylene, butylene radicals, i. e., does not exceed 4 carbon atoms.

7. Substituted aryloxyalkyl groups, the alkyl portion of which comprisesethylene, propylene, butylene radicals, i. e., does not exceed 4 carbonatoms and in which the substitution is a member of the group consistingof:

(a) OH.

(b) Ethyl, methyl, propyl and butyl.

(c) Alkoxy groups, the alkyl portion of which comprises ethyl, methyl,propyl and butyl, i. e., does not exceed 4 carbon atoms.

(d) Fluorine.

(e) Bromine.

(f) Chlorine.

(9) Amino groups.

(h) Acylamino groups, the aoyl group of which comprises formyl, acetyl,propionyl, butyryl, valeryl, caproyl, heptoyl, caprylyl, i. e., does notexceed 8 carbon atoms.

(2') Alkylamino groups, the alkyl portion of which comprises ethyl,methyl, propyl and butyl, i. e., does not exceed 4 carbon atoms.

8. Cyclopentyl and cyclohexyl groups.

9. Cyclopentylalkyl and cyclohexylalkyl groups, the alkyl portion ofwhich comprises methylene, ethylene, propylene, butylene, amylene,Ihexylene.

10. A phenyl group.

55 11. A substituted phenyl group, in which the 3 substitution is amember of thegroup consisting or:

(s) OH. V

(b) Ethyl, methyl. propyl and butyl.

(c) -Allroxy groups, the allql portion or which comprises ethyl, methyl,propyl and butyl, i. e.. does not exceed 4 carbon atoms.

(d) Fluorine.

(e) Bromine.

(I) Chlorine.

(9) Amino groups.

(h) Acylamino groups. the acyl group oi which comprises tormyl, acetyl,propionyl, butyryl, valeryl, caproyl, heptoyl and caprylyl, i. e., doesnot exceed 8 carbon atoms.

Alkylamino groups, the alkyl portion 0! which comprises ethyl, methyl,propyl and butyl, i. e.. does not exceed 4 carbon atoms.

R, Bi and R: are members of the group consisting of hydrogen and alkylgroups consisting oi methyl, ethyl, propyl, butyl, amyl and hexyl. thesubstituents for R, R1, and Rs being selected so that the sum of thecarbon atoms thereoi does not exceed six carbon atoms.

1: is a member or the group consisting of chlorine and bromine.

The inorganic and organic salts such as will be readily formed with, forexample, inorganic and organic acids, such as hydrochloric, sulfuric,sulfamic, tartaric. glycolic, phosphoric, succinic, maleic, hydrobromic,acetic, and the like, are contemplated as included within thisinvention.

The compounds contemplated by this invention may be prepared by variousprocedure. However, as generally illustrative of procedure for thepreparation or the several compounds and as exemplifying preferredprocedure for their preparation. they will variously be prepared by atwo step process which will be made apparent by the following scheme:

cm-cn-x E R1 z-N-con It will be appreciated that in the above schemeillustrative of the process for preparing compounds in accordance withthis invention X, Z, R1 and R2 represent the atoms in groups asdesignated with reference to the above general formula for the compoundscontemplated by this invention.

In proceeding for the preparation of compounds according to thisinvention, the starting material 7-chloroacenaphthene or7-bromoacenaphthene may be readily prepared by reacting 7- acenaphthenoland thionyl chloride or thionyl bromide in the presence of pyridine. Byway of example 'I-chloroacenaphthene will melt at 38-39 C.

The reaction between 'l-chloroacenaphthene or 'l-bromoacenaphthene andthe amino alcohol. i. e., the first step in the process exemplifiedabove, will be carried out conveniently in an inert solvent. such, forexample, as benzene, toluene, xylene, or the like. An excess of theamino alcohol may be used to remove the hydrogen halide formed in thereaction or. as will be obvious to those skilled in the art, anotheracid binding agent may be employed. The amino alcohol product of thefirst step may be isolated as free base by distilling oi: the solvent ormay be converted into a hydrohalide salt by obvious procedure andpurified by recrystallization.

To obtain the end product, the intermediate amino alcohol, product orthe first step of the process as illustrated, either as the free base oras a hydrohalide salt, is heated with any one of the commonly usedagents for replacing a hydroxyl group by a halogen such, for example, asthionyl chloride, thionyl bromide, concentrated hydrobromic acid.concentrated hydrochloric acid, or the like, it being, we believe,apparent that the end product is obtained from the intermediate aminoalcohol by replacing the reactive hydroxyl group with chlorine orbromine.

The p-chlorethylamine or p-bromethylamine end product is obtained as ahydrohalide salt. The salt may be readily converted to the free base byinteraction with one equivalent of a strong base, as, for example,sodium hydroxide, in usual and well known manner, for example, by theaddition of the strong base to a cold aqueous solution of the salt. Thefree base may be isolated by rapid extraction into an organic solventsuch as ether or benzene.

For the preparation or any desired inorganic or organic salt, the freebase will be reacted in usual well known manner with the appropriateinorganic or organic acid.

As more specifically illustrative of compounds in accordance with thisinvention and of specific procedure for the preparation thereof, thefollowing examples will exempliiy compounds of the several typescontemplated and procedure for the preparation thereor and will, inconnection with the foregoing general definition of the compoundscontemplated and their preparation, make apparent to those skilled inthe art the structure oi. all the several compounds contemplated by thisinvention and procedure for their preparation:

EXALCPLEI N-(7-acenaphthenul) -N-ethyl-p-chlorethulamine hydrochloridecm-cn-N-cm-cmcmc:

Seventeen grams of N-(7-acenaphthenyli-N- ethylaminoethanolhydrochloride is suspended in dry chloroform and a solution of 8.8 g. ofthionyl chloride in ml. of chloroformis added with cooling. The reactionmixture is then heated at 35 C. for one-half hour and finally heated toreflux for one and one-half hours. The solvent is removed under reducedpressure and the product N- ('Z-acenaphthenyl)-N-ethyl-fl-chlorethylamine hydrochloride is recrystallized from alcoholand ether. It meltsat 197.5-198 C.

The product obtained in the form of its hydrochloride will bereadilyconverted tothe free base by treatment thereof in cold aqueoussolution with one equivalent of sodium hydroxide in well known manner.The free base may be isolated from the mixture by quickly extracting itwith an organic solvent such as ether or benzene.

Organic and inorganic .salts will be prepared by adding the desiredorganic or inorganic acid to a solution of the free base in,-forexample, ether, in the usual and well known manner.

EXAMPLE-2 N- 7-ecendphthenul) -N-benzyl-p-chlorethylamine hydrochlorideresidue is recrystallized from n-amyl alcohol. N- r 'I-acenaphthenyl)-N-benzylfi-chloroethylamine hydrochloride melts at 196-1975 C. v

The free base and inorganic and organic salts thereof will be obtainedas heretofore made perfectly apparent.

EXAMPLE 3 N- (7-dce1 i aphthenyl) Jimihgvt-p-bhlorethylaminehydrochloride This compound will be prepared by the procedure of Example1 using an equivalent amount of methylaminoethanol instead ofethylaminoethanol.

The free base and inorganic and organic salts thereof will be obtainedas heretofore made perfectly apparent.

N- i-acena hthenul) -N@ (isodaoamyl) p-chtorethylamine hydrochloride Theprocedure of Example 1 will be used with the ethylaminoethanol replacedby an equimolar amount of isoamylaminoethanol.

The free base and inorganic and organic salts thereof will be obtainedas heretofore made perfectly apparent.

N- (7-aeenaphthen1 l) -N dllyl -p-ohlorethulamine hydrochlorideCHx-CH-N-CHr-CHz-CLHC] This compound will be made in the same manher asExample 1 except that 1-ethylamino 2- propanol will replaceethylaminoethanol in the first step of the synthesis. q The free baseand inorganic and organic-salts thereof will be obtained as heretoforemade perfectly apparent.

' EXAMPLE? N.- (7-acenap thenvl) methane-amm- 1-chloropr mnehydrochloride The procedure'of Example 1 will be followedwith2-ethylamino-1-propanol used in place of ethylaminoethanol. I

The free base and inorganic and organic salt: thereof will be obtainedas heretofore made perfectly apparent.

EXAMPLE8 OCH:

This compound will be prepared as described under Example 2 except thatp-methoxyphenylisopropylaminoethanol will be used instead ofbenzylaminoethanol.

The free base and inorganic and organic salts thereof will be obtainedas heretofore made perfectly apparent.

From the above general and specific disclosure all of theseveral'compounds and inorganic and organic salts thereof contemplatedby this invention are made perfectly apparent to those skilled in-theart, it being only necessary for the chemist to substitute the atoms andgroups, all of which are common and well known to the chemist,corresponding to any particular compound or salt thereof in the generalformulae given.

From the foregoing general and specific disclosure of procedure for thepreparation of the compounds and salts thereof contemplated by thisinvention, it is apparent to those skilled in the art that all thecompounds and salts will be prepared by the procedure described andexemplified by the mere use in step 1 of the reagents corresponding toany particular compound desired, the reagents for any particularcompound being either well known or prepared by the procedure indicatedand affording no problem to the chemist.

As ha been indicated, while in the foregoing examples the products inaccordance with this invention are exemplified by their hydrochloridesalts, the several examples will serve as specific examples of freebases by the mere elimination from the several formulae given of theradical 1101. As has been indicated, the free bases will be obtainedfrom the hydrohalide salts by usual and well known procedure comprisingtreatment with an inorganic base such as sodium carbonate, sodiumhydroxide, or the like. The above general formula will serve asspecifically exemplifying all the several compounds embraced thereby bya mere substitution in the formula for Z, R1, R: and X of thesubstituents given therefor in connection with the formula.

What we claim and desire to protect by Letters Patent is:

1. p-Haloethylamines having the structure cnr cn-N-cn-cn-x Number inwhich Z is a member of the group consisting of lower alkyl groups, loweralkenyl grou s. phenylalkyl groups. the alkyl portion of which does notexceed 4 carbon atoms. methoxy-substi- 'tuted phenylalkyl groups, thealkyl portion of which does not exceed 4 carbon atoms; R1 and R: aremembers of the group consisting of hydrogen and methyl; and X is amember of the group con-' sisting of chlorine and bromine; and acidaddition salts of said compounds. I

2. A compound having the formula:

3. A compound having the formula:

CHrCH-N-CHr-C :CLHCI 4. A compound having the formula:

CHg-CH-N-CHr-ClIs-CLHCI 5. A compound having the formula:

CHz-CH-N-CHa-CHr-CLHC] Ha ts 6. A compound having the formula:

cm ca-m-cm-cH-cmncl JALIES F. KERWIN: GLENN E. ULLYOT.

REFERENCES CITED The following references are of record in the file ofthis patent:

FOREIGN PATENTS Country Date Austria Apr. 15, 1933 OTHER REFERENCESAchenbach et al.. Fed. Proc., vol. 6, pp. 304-305. Hunt: J. Pharm. Exp.Therapy, vol. 95, pp. 177- 184.

1. B-HALOETHYLAMINES HAVING THE STRUCTURE